S

Serum autoantibodies to brain in Landau-Kleffner

variant, autism, and other neurologic disorders

Anne M. Connolly, MD, Michael G. Chez, MD, Alan Pestronk, MD, Susan T. Arnold, MD,
Shobhna Mehta, BSc, and Ruthmary K. Deuel, MD

Objective: Etiologically unexplained disorders of language and social development have often been reported to improve in patients treated with immune-modulating regimens. Here we determined the frequency of autoantibodies to brain among such children.
Design: We collected sera from a cohort of children with (1) pure LandauKleffner syndrome (n = 2), (2) Landau-Kleffner syndrome variant (LKSV,
n = 11), and (3) autistic spectrum disorder (ASD, n = 11). None had received immune-modulating treatment before the serum sample was obtained. Control sera (n = 71) were from 29 healthy children, 22 with nonneurologic illnesses (NNIs), and 20 children with other neurologic
disorders (ONDs). We identified brain autoantibodies by immunostaining
of human temporal cortex and antinuclear autoantibodies using commercially available kits.
Results: IgG anti-brain autoantibodies were present in 45% of sera from
children with LKSV, 27% with ASD, and 10% with ONDs compared with
2% from healthy children and control children with NNIs. IgM autoantibodies were present in 36% of sera from children with ASD, 9% with
LKSV, and 15% with ONDs compared with 0% of control sera. Labeling
studies identified one antigenic target to be endothelial cells. Antinuclear
antibodies with titers 1:80 were more common in children with ASD and
control children with ONDs.
Conclusion: Children with LKSV and ASD have a greater frequency of
serum antibodies to brain endothelial cells and to nuclei than children with
NNIs or healthy children. The presence of these antibodies raises the possibility that autoimmunity plays a role in the pathogenesis of language and social developmental abnormalities in a subset of children with these disorders. (J Pediatr 1999;134:607-13)

From the Departments of Neurology and Pediatrics, Washington University, St. Louis Childrens Hospital, St
Louis, Missouri; and Rush-Presbyterian Medical Center, Chicago, Illinois.

Supported by National Institutes of Health grant 1 K08 NS01648-01 and by a grant from the
Cure Autism Now Foundation.
Presented in part at the Child Neurology Society meeting, Phoenix, Arizona, October 29-November 3, 1997.
Submitted for publication Aug 25, 1998; revision received Oct 30, 1998; accepted Jan 27, 1999.
Reprint requests: Anne M. Connolly, MD, Department of Neurology, Box 8111, Washington
University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110.
Copyright 1999 by Mosby, Inc.
0022-3476/99/$8.00 + 0 9/21/97330

Pervasive development disorders are a

group of syndromes associated with abnormal cognitive, social, and language
abilities. Autistic spectrum disorders are
characterized by language and social interaction disturbances and deficits in
imagination.1 Regression of previously
normal development is sometimes reported, as with Landau-Kleffner syndrome.1,2 Although ASDs are associated with several well studied conditions
that have known genetic3,4 and acquired5,6 causes, the pathophysiology
that predicates the language and social
deficits is not understood. Furthermore,
the majority of children with ASDs have
no identified associated cause.
ANA
ASD
EEG
HC
LKS
LKSV
NNI
ONDs
PBS

Antinuclear antibody
Autistic spectrum disorder
Electroencephalogram
Healthy children
Landau-Kleffner syndrome
Landau-Kleffner syndrome variant
Non-neurologic illness
Other neurologic disorders
Phosphate-buffered saline

Abnormalities of the immune system

in children with autism have been described. Abnormal cell-mediated immunity and abnormal T-cell subsets7-18
and autoantibodies to neural antigens19-21 have been described in some
patients with ASDs. Recently, abnormal cytokine profiles with a decrease
in TH1 cytokineproducing cells and
an increase in TH2 cytokineproducing T cells have been reported.22 Some
children with ASDs show improvement with immune-modulating treatment.7,19,23-25 Given that only a subset
of patients with ASDs have demonstrated immune system abnormalities
607

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MAY 1999

Table I. Developmental criteria used to distinguish children with LKS, LKSV, and ASD

Diagnosis

Language
development
until regression

LKS

Normal

LKSV

Normal

ASD

No regression;
always abnormal

Age at
language
regression
>24 mo,
<12 y
>24 mo,
<12 y
NA

Motor
skills
Normal
Normal or mild
abnormalities
Normal or mild
abnormalities

Social
skills
Normal or mild
abnormality
Mild to
severe
abnormality
Severe
abnormality

NA, Not applicable.

Table II. Summary of clinical data for children with LKS, LKSV, and ASD and control
subjects

Diagnosis
LKS (n = 2)
LKSV (n = 11)
ASD (n = 11)
OND (n = 20)
NNI/HC (n = 51)

Age at
testing (y)

Sex

Age at language
regression (y)

2.3, 3.5
6.5 1.6
4.7 2.8
6.8 3.1
4.1 2.2

1 M, 1 F
7 M, 4 F
7 M, 4 F
11 M, 9 F
28 M, 25 F

2.0, 2.1
2.4 0.5
NA
NA
NA

NA, Not applicable.

or have responded to immune-modulating treatment, it is unlikely that an

immune disorder is the only or primary factor in ASD symptom pathogenesis. Nevertheless, the findings have led
investigators to consider new multifactorial models for the pathogenesis of
autism.22,26,27
LKS or acquired epileptic aphasia is
characterized by the subacute onset of
an isolated language disturbance associated with an epileptiform electroencephalogram and/or a few seizures.28-34
In classic reports, the childs language
and all other development is normal before the onset of the convulsive disorder.35,36 Some authors have suggested
that LKS overlaps clinically with
rolandic epilepsy, continuous spike
wave discharges in slow-wave sleep,37
and acquired epileptiform opercular
syndrome.33 Others are willing to extend the broad LKS category to include
children with autistic regression as long
608

as they have epileptiform EEGs (particularly during sleep).29,38 We have

termed this more broadly defined syndrome the Landau-Kleffner syndrome variant. Striking improvement in language
function in patients with LKS and
LKSV after treatment with immunomodulating agents has been reported by
some authors,31,39,40 but not all.32
Because children with either ASD or
LKSV exhibit cognitive abnormalities
that have been reported to respond to
various forms of immune-modulating
treatment, we investigated the frequency of autoantibodies to brain in
both disorders.

mild to severe social skills abnormalities. Whole blood was drawn and centrifuged. The serum was decanted and
frozen until assay.

Immunocytochemistry
Frozen sections of normal human
temporal lobe cortex (8 m thick)
were placed on glass slides, dried
overnight, fixed with acetone for 20
minutes, and blocked with 100% normal goat serum for 1 to 2 hours. Sections were incubated with test sera (diluted 1:100 in 10% normal goat serum)
at 4C overnight in a humidity chamber, washed with phosphate-buffered
saline 3 times, incubated with peroxidase-conjugated goat anti-human IgM
(1:200) in PBS for 4 hours, washed
again with PBS 3 times, and developed
with 0.05% 3,3-diaminobenzidine and
0.01% hydrogen peroxide in PBS.
Each slide was independently examined for staining patterns by 2 observers (A.M.C. and A.P.) who had no
knowledge of clinical diagnosis. A
score of 0, 1+, 2+, or 3+ was assigned
to each sample based on degree of
staining. Samples were considered
positive if staining was scored 2+ or 3+
compared with a standard negative
control made from the pooled sera of
healthy blood donors. All samples with
a score of 2+ or 3+ were further diluted
to 1:200, 1:400, and 1:800.

Identification of ANA Patterns

The Kallestad quantafluor kit (Sanofi
Diagnostics) was used to determine
and characterize the ANAs present in
the childrens sera.41,42 Staining patterns were examined and characterized
by 2 blinded observers (A.M.C. and
S.M.) without knowledge of the clinical categorization. We considered an
ANA titer of 1:80 abnormal.43

METHODS

Classification of Children

Informed consent for a blood sample

was obtained from parents of children
presenting with severe communication
disorders coupled with seizures and

Clinical diagnoses were assigned after

examination of the medical records by
reviewers blinded to the immunostaining results (S.A. and R.K.D.). No child
had been treated with immunosuppres-

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VOLUME 134, NUMBER 5
sive medications before the time that
the serum sample was obtained. Sera
were collected from 3 other groups of
children: (1) children with acute or
chronic non-neurologic illnesses (NNI
group, n = 24), (2) children with other
neurologic disorders with (n = 10) or
without (n = 10) epilepsy but not primary language or social skills disorders
(OND group), and (3) healthy children
(n = 29).
We assigned the diagnoses of LKS (n
= 2; age 2.3 and 3.5 years) LKSV (n =
11; age 6.5 1.6 years), and ASD (n =
11; age 4.7 2.2 years) based on clinical data that included developmental
history, seizure history, neurologic examination, and EEG findings (Tables I
and II). A diagnosis of classical LKS
was assigned to children who displayed
regression of previously clearly normal
language skills with retained normal
motor and social skills. They could
have no or few clinical seizures. Moderate to severe epileptiform abnormalities on EEGs, which were recorded for
a minimum of 4 hours and included
awake, drowsy, and sleep states, were
required. These clinical criteria allow a
definition of LKS as it was originally
described, which has been advocated as
important in clinical trials.30,35
The diagnosis of LKSV required a
period of clearly normal function until
regression of language and social skills
after age 24 months, leaving the child
with language abnormalities and variably severe abnormalities in social
skills (Table I). EEGs were required to
show moderate to severe epileptiform
abnormalities.
A diagnosis of ASD was assigned to
children who had never had normal
language or social skills (ie, had no history of regression). Clinical seizures or
epileptiform abnormalities on EEG did
not exclude children from the ASD
category.
Our choice of regression after 2
years of age as the point of separation
between LKSV and ASD was made
with the knowledge that regression
after a period of brief normal function

Fig 1. A, IgG antibodies from a child with LKSV binding to small blood vessels in human temporal
lobe cortex (original magnification 80). Immunostaining (1:100) demonstrates distinct capillary
staining. B, Control serum shows no specific labeling.

may occur in ASD.2 In contrast, regression always occurs in LKS. Thus

our operational definitions of LKSV
and ASD were not fully inclusive. For
example, a child with language and social regression at 18 months would not
fulfill clinical criteria for either of our
study groups.

Exclusion Criteria
We excluded children from the LKS,
LKSV, or ASD categories if they had a
known brain tumor, diffuse or focal
hypoxic ischemic brain injury, central
nervous system infection, or traumatic
brain injury. Although they were not
specifically excluded, our sample included no children with known genetic
diseases associated with autism such as
fragile X syndrome.

Statistical Analysis
Patient characteristics including diagnosis, age at time sample was obtained, sex, age of regression, clinical
seizures, epileptiform EEGs, and IgG
and IgM antibody staining and ANA
results were entered into a spreadsheet
(Microsoft Excel). Descriptive statistics for each of the 6 original groups of
children (LKS, LKSV, ASD, OND,
NNI, and HC) were performed. Fisher exact tests were used to compare the
incidence of positive (rated 2+ or 3+ by
2 blinded observers) antibody-positive
sera among the patient and control

groups. A P value of .05 was considered significant.

RESULTS
Clinical Features (Tables II-VI)
After chart review by blinded observers (S.A. and R.K.D.), 24 children
who presented with language and communication disorders coupled with
seizures or EEG abnormalities and/or
social skills deficits were classified as
having LKS (n = 2), LKSV (n = 11),
and ASD (n = 11). A few clinical
seizures occurred in both patients with
LKS. Although all 11 patients with
LKSV had moderate to severe epileptiform abnormalities on EEGs, only one
had seizures. None of the children with
ASD had seizures, although various
types of EEG abnormalities occurred
in 9 of 11.

IgG and IgM Immunostaining

on Human Cortex
The majority of the positive sera had a
very similar pattern of immunostaining
on human cortex. A representative sample is shown in Fig 1, A (patient 3; clinical diagnosis, LKSV). The pattern and
distribution of sera staining of IgG and
IgM antibodies in brain corresponded
best to capillaries. We next used a commercially available mouse anti-human
antibody that recognizes human CD31,
a surface component of human endothe609

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MAY 1999

Fig 2. A, Human cortex stained with sera IgG from a patient with LKSV (original magnification
40). B, A serial section is shown demonstrating the pattern recognized by the mouse anti-human
CD-31 antibody after a goat anti-mouse peroxidaselabeled secondary antibody was added (Jackson Immuno Research) (original magnification 40).The arrowhead in each panel identifies a large
vessel darkly stained by both human sera and CD31 monoclonal antibody. Arrows identify smaller
capillaries cut in different planes. Staining patterns are nearly identical, confirming that one antigenic
target is human brain endothelial cells.
Table III. Clinical, immunostaining, and ANA data for children with LKSV

Patient
No.
1
2
3
4
5
6
7
8
9
10
11

Age
(y)

Sex

Intellectual
development

IgG

IgM

ANA titer/
pattern

4.1
6.3
8.8
6.2
5.0
3.9
5.4
6.0
6.6
7.6
8.9

M
F
F
F
M
M
M
M
F
M
M

Normal
Severely delayed
Normal
Normal
Normal
Normal
Mildly delayed
Normal
Mildly delayed
Severely delayed
Mildly delayed

+++

++
+++

++
++

++

1:80 speckled

1:1280 speckled

Table IV. Clinical, immunostaining, and ANA data for children with ASD

Patient
No.
1
2
3
4
5
6
7
8
9
10
11

610

Age
(y)

Sex

Intellectual
development

IgG

IgM

3.6
3.2
8
3.8
8.6
4.5
3.3
3.8
3.7
1.8
6.9

F
F
M
M
F
F
M
M
M
M
M

Severely delayed
Severely delayed
Mildly delayed
Severely delayed
Severely delayed
Normal
Severely delayed
Severely delayed
Severely delayed
Severely delayed
Mildly delayed

+++
++

++

++
++
++

++

ANA titer/
pattern

1:1280 speckled
1:80 speckled

1:320 nuclear

lial cells (Jackson Immuno Research)

on the next serial section. The pattern
was the same (Fig 2, B). This confirmed
that one antigenic target was indeed
human endothelial cells.
Two sera from the LKSV group
(Table III) and 3 from the ASD group
(Table IV) also showed immunostaining of glial and neuronal nuclei. These
patients were subsequently shown to
have positive ANAs by routine testing.
Statistical analysis of the incidence of
immunostaining in the various patient
and control groups showed no significant difference between the HC and
NNI control groups. These groups
were therefore combined into the
NNI/HC group, which was then compared with the other groups. The
OND group of children did differ from
the HC and NNI children; therefore, it
was analyzed separately.
Neither child with classically defined
LKS had autoantibodies to brain or
nuclei. Given that there were clinical
differences among the children with
LKS, LKSV, and OND and that the
number of children with LKS was too
small to be informative, we omitted the
2 children with LKS from the rest of
our statistical evaluations.
Immunostaining and ANA results
for the children with LKSV, ASD, and
ONDs are summarized in Tables III,
IV, and V and compared in Table VI.
Sera from children with LKSV and
ASD showed significantly more IgG
staining compared with the NNI/HC
control subjects (P .004 and P = .02).
However, only sera from the ASD
group showed more IgM immunostaining compared with these control
groups (P = .001). In the OND group,
3 of 20 (15%) had positive IgM immunostaining (P = .02) and 2 of 20
(10%) had positive IgG staining (P =
.19) compared with the NNI/HC
group (Table VI). We analyzed this
neurologic group further to try to determine whether any specific clinical
characteristics might correlate with the
positive samples. There was no significant difference in age, sex, or presence

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Table V. Clinical diagnosis, immunostaining, and ANA data of children with other neurologic disorders

Patient No.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20

Sex

Age
(y)

M
F
M
F
M
F
F
M
M
F
F
F
M
M
M
M
M
F
F
M

0.3
1.2
1.6
4.3
4.4
5.4
5.8
6.6
6.8
7.4
7.7
7.7
7.9
8.5
9.1
9.1
9.8
9.9
10.4
11.4

Seizures
+
+

+
+
+
+
+
+

+
+

Development
Normal
Global delay
Normal
Normal
Normal
Normal
Normal
Normal
Global delay
Global delay
Normal
Global delay
Global delay
Global delay
Global delay
Normal
Normal
Global delay
Global delay
Normal

IgG

IgM

ANA pattern/
titer

Tremor

Schizencephaly

ADD

Epilepsy

Acquired neuropathy

Absence seizures

Epilepsy

Acute cerebellar ataxia

Idiopathic MR

Idiopathic MR

Absence seizures

Idiopathic MR

Idiopathic MR
++
Idiopathic MR

ADD
++
ADD

ADD

Lennox-Gastaut syndrome
Idiopathic MR

ADD

++

++

++

1:640 Speckled

1:80 Speckled

Diagnosis

ADD, Attention deficit disorder; MR, mental retardation.

of clinical seizures. All 5 children with

positive serum antibodies had global
developmental delay (in all cases idiopathic) (5 of 9 or 55%) compared with
no positive sera from children with
normal development (0 of 11; P =
.008).
On further dilution, all samples assigned a score of 3+ had positive immunostaining with titers 1:800. All
samples with a 2+ score had positive
immunostaining with titers ranging between 1:200 and 1:400.

Table VI. Human cortex staining and ANAs from children with LKSV, ASD, and
control children

ANAs

children suggests that a more widespread activation of the immune system may be present in these children.
Indeed, both children in the LKSV
group with positive ANAs also had
positive endothelial staining. Two of
the 3 children in the ASD group with
positive ANAs had positive endothelial
antibody staining. However, neither of
the 2 children with positive ANAs in
the OND control group had positive
immunostaining (Table VI).

Neither child with LKS and none of

the NNI/HC control patients had positive ANAs. Sera from 2 children in the
LKSV group and 3 in the ASD group
had positive ANAs (P = .03 and P = .004,
respectively, compared with the NNI/
HC groups). Two children in the OND
group also had positive ANAs, although
that frequency did not reach significance compared with the NNI/HC
group. The presence of ANAs in some

Diagnosis
LKSV (n = 11)
ASD (n = 11)
OND (n = 20)
NNI/HC (n = 51)

Cortex IgG
staining [no. (%)]

Cortex IgM
staining [no. (%)]

ANA >1:40
[no. (%)]

5 (45%)*
3 (27%)
2 (10%)
1 (2%)

1 (9%)
4 (36%)*
3 (15%)
0 (0%)

2 (17%)
3 (27%)*
2 (10%)
0 (0%)

*P = .004 compared with the NNI/HC group.

P = .03 compared with the NNI/HC group.
P = .02 compared with the NNI/HC group.

DISCUSSION
Previous studies show various abnormal immune responses in children with
autism or LKS. For example, a proportion of patients with ASD have T-cell
dysfunction or abnormal numbers of T
cells.10,12,14,16,19 LKS has been associated with infections or postinfectious
processes in several patients.40,43 Central nervous system targets of autoantibodies, including myelin basic protein9
611

CONNOLLY ET AL

and neurofilament protein,19 have been

identified in autistic patients. However,
these autoantibodies are not specific to
autism, because myelin basic protein
autoantibodies are found in patients
with multiple sclerosis and neurofilament protein autoantibodies are also
found in household contacts of autistic
children.19 In a study in which whole
brain homogenate was used (and therefore specific target cells could not be
identified), anti-brain IgG autoantibodies were present in similar incidence in
sera from healthy subjects and clinically depressed patients, as well as in
autistic patients.21 Disturbance in autoimmunity with reaction to myelin
proteins was shown in 4 children with
LKS.40 Many of these previous studies
did not report neurologic controls.
In our work, we asked first whether
immunostaining of brain by sera from
children with language and social skills
abnormalities would occur. We assigned an operationally defined diagnosis of LKS, LKSV, or ASD after a
blinded review of the records of 24 children who presented with communication or language disorders coupled with
seizures and adequate assessment of social skills. The studies showed that autoantibodies to brain were common in
both the ASD and LKSV groups, but
they were very uncommon in the
HC/NNI group. The cellular target of
the predominant IgG and IgM autoantibodies was identified as endothelium
by serial section labeling experiments.
This demonstrated that the pattern of
reactivity of the childrens sera was
nearly identical to the pattern recognized by a commercial antibody to
CD31, a marker of endothelial cells
(Fig 2). The number of children with
classical LKS, a relatively rare condition, was too small for us to draw any
conclusions concerning the frequency
of cases with autoantibodies. In the 20
children with ONDs, 5 also had autoantibodies to brain as determined by
immunostaining. Thus although the antibodies we found were of higher frequency in the children with LKSV or
612

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MAY 1999
ASD, they were not specific to any one
symptom of LKSV or ASD.
A few children in each of the 3 neurologically abnormal groups also
showed positive ANAs. Positive ANAs
are nonspecific because they have been
reported in a variety of immune diseases and in children with chronic nonspecific illnesses.42 However, although
nonspecific, our data and others show
that titers 1:80 are rare in healthy
children.42
In summary, IgG autoantibodies to
endothelial cells are common in sera
from children with LKSV and ASD
and also occur in a lower percentage of
sera from those with ONDs. Serum
IgM antibodies to endothelial cells are
common in patients with ASDs and
ONDs, particularly those with global
developmental delay. The fact that
these antibodies are rare in sera from
healthy children or those with NNIs
raises the possibility that these antibodies may be related to symptoms in
some children. The current data serve
more to provoke further questions
concerning autoimmunity vis-a-vis language and social skills disorders than
to answer any. The finding of anti-endothelial autoantibodies in the sera of
only about half of patients suggests
that either these antibodies may not be
related to the pathogenesis of the
symptoms, even in antibody-positive
patients, or that these antibodies are
directly or indirectly related but only
in a subset of affected children. If so,
other properties such as absolute titer
or ability of antibodies to fix complement may be more important than simple detection in serum. Clinically, further assessment of the effectiveness of
immune-modulating treatments of children with demonstrable antibodies
may also help determine whether antibodies are relevant to pathogenesis in
affected children.

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